ABSTRACT In order to realize the promise of precision medicine, more and better biomarkers are needed to guide clinical decision making. This is of particular importance for patients with colorectal cancer (CRC) as: 1. CRC is the third most common cancer in both men and women accounting for 9% of all incident cancers in the United States; 2. The 5-year survival rates for the most common cancers in men and women, prostate and breast cancer, are 99% and 89%, respectively, but is only 64% for CRC making it the second most common cause of cancer related death in the U.S.; 3. At present there is a lack of clinically useful biomarkers predictive of recurrence or survival for CRC patients that can be used to guide surveillance and treatment. Consequently, there are issues of both overtreatment and undertreatment because treatment is based largely on clinical and pathologic parameters, but little else to risk stratify patients. This study will utilize 1,574 participants in a multi- center prospective cohort (the ColoCare Study) of newly diagnosed CRC patients. Detailed demographic, clinical, epidemiologic, and follow-up data are ascertained on all participants along with blood samples collected at multiple time points. Thus, this study is specifically designed to meet the overarching goal of this proposal, the discovery and verification of novel blood-based biomarkers predictive of recurrence among CRC patients, through achieving the following specific aims: 1. Discovery and verification of novel biomarkers predictive of recurrence among CRC patients: Utilizing samples collected at the time of diagnosis we will evaluate the plasma proteome, glycome, and autoantibody repertoire, including assessment of promising markers reported in the literature, using well-validated laboratory approaches to identify markers predictive of risk of recurrence for well-defined clinical applications (predicting recurrence in stage I/II patients and in stage III patients). Top candidates from our discovery experiments meeting particular statistical criteria will be evaluated in a group of patients completely separate from those used in the discovery set. 2. Discovery and verification of novel biomarkers useful for the early detection of CRC recurrence: Utilizing serial samples collected at regular intervals post-diagnosis we will discover novel biomarkers potentially useful for disease monitoring using proteomic, glycomic, and autoantibody platforms. Markers will be evaluated in the context of CEA, a clinically used biomarker of recurrence that has a 60% sensitivity and 90% specificity for detecting recurrent colorectal cancer in stage II and III patients. If successful this project could lead to the development of clinical grade biomarker assays that could have significant impact on reducing the morbidity and mortality associated with colorectal cancer. This study is innovative in that the cohort that will be used is unique, highly characterized, and possesses serial samples collected at regular intervals; the unique platforms that will be used have been shown to yield potentially useful biomarkers and can also evaluate existing markers of interest; and this study is powered to identify biomarkers with clinically meaningful performance characteristics.